Genetics of Osteoporosis: Perspectives for Personalized Medicine

Wen-Feng Li; Shu-Xun Hou; Bin Yu; Dan Jin; Claude Férec; Jian-Min Chen


Personalized Medicine. 2010;7(6):655-668. 

In This Article

Abstract and Introduction


Osteoporosis is the most common metabolic bone disorder worldwide. At least 15 genes (e.g., ESR1, LRP5, SOST, OPG, RANK and RANKL) have been confirmed as osteoporosis susceptibility genes, and another 30 have been highlighted as promising susceptibility genes. Notably, these genes are clustered in three biological pathways: the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway and the RANK/RANKL/osteoprotegerin (OPG) pathway. In this article, using data pertaining to these three biological pathways as examples, we illustrate possible principles of personalized therapy for osteoporosis. In particular, we propose to use inhibitors (e.g., denosumab) of the RANK/RANKL/OPG signaling pathway to circumvent resistance to estrogen-replacement therapy: a novel idea resulting from the consideration of a mechanistic link between the estrogen endocrine pathway and the RANK/RANKL/OPG signaling pathway. In addition, we call for more attention to be focused on rare variants of major effects in future studies.


Osteoporosis is characterized by compromised bone strength, and consequently, increased risk of fracture. It is the most common metabolic bone disorder worldwide; approximately 50% of women and 20% of men aged older than 50 years will experience one or more osteoporotic fractures in their remaining lifetime.[1] In principle, osteoporosis could result from:

  • A failure to achieve a skeleton of optimal strength during growth and development;

  • Excessive bone resorption resulting in loss of bone mass and disruption of architecture;

  • A failure to replace lost bone due to defects in bone formation.[2]

The risk of osteoporosis is influenced by many factors such as age, sex, diet, physical activity, medication use and menopausal status, but one of the most important clinical risk factors is a positive family history, underscoring the role of genetic factors in determining disease susceptibility.[3] Recently, we provided a comprehensive review of advances made over the past 15 years with respect to the discovery of osteoporosis causing genes. We noted an accelerating pace in identifying and validating osteoporosis susceptibility loci in the past 4 years, which was largely attributable to the use of genome-wide association studies (GWASs). Based upon a combined examination of the available data, we concluded that there are at least 15 confirmed genes (e.g., ESR1, LRP5, SOST, OPG, RANK and RANKL) and potentially another 30 genes or more that could be assigned as osteoporosis susceptibility genes. Notably, these genes are clustered into three biological pathways: the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway and the RANK/RANKL/osteoprotegerin (OPG) pathway.[4] Since the publication of our review, GWASs have identified two novel osteoporosis genes, ALDH7A1[5] and JAG1;[6] two further comprehensive reviews on the genetics of osteoporosis have also been published.[7,8]

As we highlighted previously, the ultimate promise of osteoporosis genetics is not only to better define the disease process, but more importantly, to lead to better preventive and therapeutic interventions.[4] Indeed, with rapid advances in next-generation sequencing techniques,[9,10] we are at a turning point in medical genetics. Notably, whole-genome sequencing has the potential to identify all disease-associated variants, particularly those rare variants that confer a major effect on phenotype expression; rare variants are of paramount relevance for personalized medicine, but so far they have often been overlooked by genotype-based analyses.[11] In this regard, it is worth emphasizing a specific point. At present, neither of the two direct-to-consumer companies – 23andMe (CA, USA)[201] and Navigenics (CA, USA)[202] – test risk markers for osteoporosis, apparently this is because the currently recognized osteoporosis-associated variants are almost invariably common polymorphisms with a modest effect.[4]

It is hoped that a catalogue of most disease-associated DNA variants for the best-studied complex conditions, such as cardiovascular disease, diabetes and autism, will be available in the next decade.[12] We hope this might also be the case for osteoporosis, given the continuing efforts of many dedicated researchers around the world. With this in mind, we shall discuss the potential implications of osteoporosis genetics on personalized medicine with a focus on individualized drug therapy. Our basic premises are:

  • Causative variant(s) with well-defined biological functions will be identified for any single patient in the foreseeable future;

  • This detailed knowledge of all main risk variants will guide the selective use of medication.

For reasons of simplicity, we shall use findings concerning the aforementioned three biological pathways as examples to illustrate the general principles.


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